Uterine leiomyomas (fibroids) are the leading indication for hysterectomy in the United States. Despite the morbidity and high medical costs associated with fibroids, there has been little epidemiologic study of this condition in the United States. Uterine leiomyomas are histologically identifiable as benign smooth muscle tumors with varying amounts of associated fibrous tissue. Many women have more than one uterine leiomyoma, but each appears to be clonally distinct. Several specific cytogenetic changes have been identified in tumor tissue, but most show no chromosomal abnormalities. These benign tumors are hormone-dependent. They develop after puberty and regress after menopause. Both estrogen and progesterone are considered important stimulants, or at least permissive factors for tumor growth. To address the research needs in this field we have designed three studies. The first is a large epidemiologic study, the NIEHS Uterine Fibroid Study, designed to 1) estimate the age-specific cumulative incidence of leiomyomas in black and white women, aged 35-49, 2) identify risk factors for the condition, 3) compare growth mediating factors in tumor and matching myometrial tissues collected at time of hysterectomy, and 4) to identify factors associated with development of fibroid symptoms including pelvic pain and uterine bleeding. The second study (Shyamal Peddada, PI) is a clinical study of fibroids designed to describe fibroid growth and compare the growth-mediating factors in growing vs nongrowing tumors. The third study monitors fibroid change with pregnancy and postpartum uterine regression. After estimating the age-specific incidence of uterine fibroids for black and white women, we began to examine risk factors for uterine fibroids. Pregnancy is protective, though not those that occur before the mid twenties. Alcohol appears to increase risk. In two cases we have replicated findings from animal models of fibroids. We find that the location of fibroids is somewhat different for parous and nonpauous women, and that prenatal exposure to DES is associated with increased development of fibroids. Increasing LH is associated with increased prevalence of the tumors, though LH may not be having direct proliferative effects, as we had hypothesized. We find no evidence for increased risk of fibroids with oral contraceptive use or with variability in menstrual-cycle length. We also explored our data on body fat and exercise. We find a small increase in risk with increased BMI (similar to other studies), and we also find that exercise is protective. As in the recent cohort analyses, smoking was not associated with risk in our data. We also collected questionnaire data for exploratory analyses on early-life exposures and several environmental/occupational exposures. While few factors showed associations with fibroid development, we did find an association of childhood use of insect repellent with fibroids. This may merit further investigation given the possible link between insect repellents and breast cancer. We measured fasting insulin and IGF-I in blood specimens collected from participants, hypothesizing both would be risk factors for fibroids. Surprisingly both tended to be protective, and diabetics were actually significantly less likely to have fibroids. For the clinical study of fibroid growth we are working at determining accurate volumetric measures of nearly 600 tumors so that we can model growth. We have completed microarrays of tumor vs normal myometrium, and we are analyzing those data. Our first manuscript is in preparation; it compares characteristics of participnats who had surgery or uterine artery embolism during the 1-year study followup with those who did not. The third study, monitoring fibroid change during postpartum uterine regression, is still in the field. We have enrolled approximately 150 of the target 400 women.